PROJECT SUMMARY/ABSTRACT The incidence of diabetes in the US population has been rapidly increasing over the past several decades. Both Type 1 and Type 2 diabetes pathophysiologies converge on failure of the insulin-producing pancreatic ?-cells. While there are a variety of known triggers for ?-cell apoptosis, most feed into pathways that lead to increased generation of reactive oxygen species (ROS) in the ?-cell. A maladaptive response to ROS results in cellular oxidative stress and subsequent cell death, likely playing a significant role in diabetes pathogenesis. In fact, oxidative stress is a common feature of both type 1 and type 2 diabetes. In my K01 studies, we found that the pleiotropic cytokine interleukin 6 (IL-6) exerts a protective effect from ?-cell apoptosis through the stimulation of autophagy. Further, we found that IL-6/autophagy signaling is reduced in islets from diabetic human donors, and have recently observed that exogenous IL-6 treatment reduces the amount of islet and ?- cell ROS generated by proinflammatory cytokines through the coupling of autophagy to antioxidant response. In this proposal, we seek to expand our studies into models of type 1 diabetes and test the hypothesis that both autophagy and antioxidant response are required for ?-cell survival under conditions of increased ROS in the ?- cell. The proposed work will incorporate both in vitro experiments using cultured islets/ ?-cells and in vivo analyses with mouse models of insufficient autophagy/antioxidant signaling and diabetes. We will pursue the following specific aims: 1. Determine how the coordination of autophagy and antioxidant response controls ?- cell survival. 2. Elucidate mechanism(s) of IL-6-mediated regulation of ROS. Overall, these experiments will define the role of autophagy/antioxidant response coupling in the adaptive response to stress and allow us to identify therapeutic targets guiding the signaling events within the islet under conditions known to lead to ?-cell failure. My background in ?-cell biology and resources within the Indiana Center for Diabetes and Metabolic Diseases makes me uniquely suited to accomplish the aims of this project, which will generate exciting preliminary data towards subsequent R01 funding.